Topical administration of pharmacologically active bases for skin lightening

ABSTRACT

Provided are methods and topical pharmaceutical formulations for skin lightening. The invention involves the topical administration of a pharmacologically active base in a formulation having a pH of about 7.5 to about 13.0, preferably about 8.0 to 11.5, and most preferably about 8.5 to 10.5. These basic formulations can be used to treat regions of hyperpigmented skin, comprising, as examples, age spots, freckles, disease-related hyperpigmented skin, melasma related to pregnancy or the use of oral contraceptives, and hyperpigmented skin due to chemical exposure or ingestion.

TECHNICAL FIELD

[0001] This invention relates generally to methods and pharmaceuticalformulations for skin lightening, and relates more particularly to theuse of a pharmacologically active base in such methods and formulations.

BACKGROUND

[0002] Cosmetically disfiguring skin pigmentation irregularities anddisorders are common and widespread, leading to a large demand for skinlightening products. The color of normal human skin is due primarily tomelanin, hemoglobin, and carotenoids. Of these pigments, melanin is ofparticular importance in regard to skin pigmentation and cosmetology.The type and amount of melanin synthesized by the melanocyte(melanin-producing skin cell), and its distribution pattern in thesurrounding keratinocytes, largely determine skin color. Two types ofmelanin are present in human skin: (1) eumelanin, which is the darkbrown pigment found in most skin, hair, and eyes, and whose productionis stimulated by exposure to ultraviolet light, and (2) pheomelanin,which is a yellow-orange pigment found mainly in the skin of veryfair-skinned people, particularly those with red hair.

[0003] A basic understanding of the pigmentation pathway is helpfulprior to the discussion of the skin-lightening agent used in conjunctionwith the method of the present invention. Melanin forms through a seriesof oxidative reactions involving the amino acid tyrosine in the presenceof the enzyme tyrosinase. Tyrosinase converts tyrosine todihydroxyphenylalanine (DOPA) and then to dopaquinone. Subsequently,dopaquinone is converted to dopachrome through auto-oxidation, andfinally to dihydroxyindole or dihydroxyindole-2-carboxylic acid (DHICA)to form eumelanin. The latter reaction occurs in the presence ofdopachrome tautomerase and DHICA oxidase. In the presence of cysteine orglutathione, dopaquinone is converted to cysteinyl DOPA or glutathioneDOPA; subsequently, pheomelanin is formed.

[0004] Skin hyperpigmentation (or melasma) has a variety of causes,including exposure to ultraviolet (UV) light, genetic makeup, wounds,age (“age spots”), pregnancy (“mask of pregnancy” or “chloasma”), oralcontraceptive use, exposure to certain chemicals, a number of skin andsystemic diseases, and other factors. A safe and effective topicalskin-lightening formulation is particularly useful for treating any suchlocalized epidermal hyperpigmentation. Such a formulation is also usefulfor masking areas of skin hypopigmentation, such as in vitiligo ortrauma-induced hypopigmentation, by lightening the surrounding skin.There is clearly a need for a safe and effective technique to reduce thedegree of skin pigmentation in such cases.

[0005] Within the art of depigmentation, hydroquinone is one of the mostwidely prescribed agents worldwide. However, due to reports of potentialmutagenicity and of widespread ochronosis in African nations, there hasbeen an increasing impetus to find alternative herbal and pharmaceuticaldepigmenting agents. In fact, hydroquinone has been banned in Europe foruse as a depigmenting agent. Other skin depigmentation agents, likeazalaic acid, kojic acid, and certain -hydroxy acids, have been used,but all have shown varying levels of local irritation.

SUMMARY OF THE INVENTION

[0006] It is accordingly a primary object of the invention to addressthe above needs in the art by providing a novel method and formulationfor skin lightening.

[0007] It is another object of the invention to provide a method andpharmaceutical formulation for skin lightening, involving a topicallyapplied formulation consisting essentially of a pharmacologically activebase, at least one pharmaceutically acceptable topical carrier, andoptionally at least one excipient, wherein the pharmacologically activebase is preferably present in an amount effective to provide theformulation with a pH in the range of about 7.5 to 13.0, and/or in anamount effective to provide a pH in the aforementioned range at the skinsurface, following topical application of the formulation. Theformulation may be a lotion, cream, solution, paste, or the like, or maybe contained in a skin patch comprised of a laminated composite intendedfor long- term adhesion to the body surface (typically throughout adelivery period in the range of about 8 to about 72 hours) in the regionof the affected area.

DETAILED DESCRIPTION OF THE INVENTION

[0008] I. Definitions and Nomenclature

[0009] Before describing the present invention in detail, it is to beunderstood that this invention is not limited to specificpharmacologically active bases, carriers, formulation types, treatmentregimens, and so forth, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting.

[0010] It must be noted that, as used in this specification and theappended claims, the singular forms “a,” “an”, and “the” include pluralreferents unless the context clearly dictates otherwise.

[0011] The terms “pharmacologically active agent,” “pharmacologicallyactive base,” and “active agent” are used interchangeably herein torefer to a basic compound or composition of matter that, when topicallyadministered to a human patient, induces a desired pharmacologic and/orphysiologic effect by local and/or systemic action, i.e., skinlightening. Also included are derivatives and analogs of those compoundsor classes of compounds specifically mentioned that also induce thedesired effect.

[0012] By “pharmaceutically acceptable,” such as in the recitation of a“pharmaceutically acceptable carrier” or a “pharmaceutically acceptablederivative,” is meant a compound that is not biologically or otherwiseundesirable, i.e., the compound may be incorporated into a topicalformulation of the invention and administered to a patient withoutcausing any undesirable biological effects or interacting in adeleterious manner with any of the other components of the formulationin which it is contained. A “pharmacologically active” compound refersto an active agent as defined above, or to an analog or derivativethereof having the same type of pharmacological activity as the parentcompound.

[0013] The terms “treating” and “treatment” as used herein refer toreduction in severity and/or frequency of symptoms, elimination ofsymptoms and/or underlying cause, prevention of the occurrence ofsymptoms and/or their underlying cause, and improvement or remediationof damage. The present method of “treating” a patient, as the term isused herein, thus encompasses both prevention of hyperpigmentation in apredisposed individual and skin lightening in a clinically symptomaticindividual.

[0014] The terms “hyperpigmented region” and “affected area” are usedinterchangeably herein to mean a localized region having high melanincontent. Examples include, but are not limited to, age spots, melasma,chloasma, freckles, disease-related hyperpigmentation, and postinflammatory pigmentation, sun-induced pigmented blemishes.

[0015] The term “skin lightening” as used herein means decreasing thepigment content of skin, usually the melanin content, including one ormore of: overall lightening of basal skin tone, and lightening ofhyperpigmented regions (melasma), including age spots, chloasma,freckles, disease- related hyperpigmentation, and post inflammatoryhyperpigmentation of sun-induced pigmented blemishes.

[0016] The term “base” is used in its traditional sense, i.e., asubstance that dissolves in water to produce hydroxide ions. The wateris typically an aqueous fluid, and may be natural moisture at the skinsurface, or the patch or composition that is used may contain addedwater, and/or be used in connection with an occlusive backing.Similarly, any liquid or semisolid formulation that is used ispreferably aqueous or used in conjunction with an overlayer of anocclusive material. Any base may be used provided that the compoundprovides free hydroxide ions in the presence of an aqueous fluid. Basescan provide free hydroxide ions either directly or indirectly and thuscan also be referred to as “hydroxide-releasing agents”.Hydroxide-releasing agents that provide free hydroxide ions directly,typically contain hydroxide groups and release the hydroxide ionsdirectly into solution, for example, alkali metal hydroxides.Hydroxide-releasing agents that provide free hydroxide ions indirectly,are typically those compounds that are acted upon chemically in anaqueous environment and the reaction produces hydroxide ions, forexample metal carbonates or amines.

[0017] By an “effective” amount or a “therapeutically effective amount”of a pharmacologically active agent is meant a nontoxic but sufficientamount of the drug or agent to provide the desired effect, i.e.,prevention or skin lightening treatment. The amount that is “effective”will vary from subject to subject, depending on the age and generalcondition of the individual, mode of administration, and the like. Thus,it is not always possible to specify an exact “effective amount.”However, an appropriate “effective” amount in any individual case may bedetermined by one of ordinary skill in the art using routineexperimentation.

[0018] The term “topical administration” is used in its conventionalsense to mean delivery of a topical drug or pharmacologically activeagent to the skin or mucosal tissue, as in, for example, skin lighteningtreatment for hyperpigmentation.

[0019] The term “body surface” is used to refer to skin or mucosaltissue.

[0020] “Carriers” or “vehicles” as used herein refer to pharmaceuticallyacceptable carrier materials suitable for topical drug administration.Carriers and vehicles useful herein include any such materials known inthe art that are nontoxic and do not interact with other components ofthe composition in a deleterious manner.

[0021] The term “aqueous” refers to a formulation that contains water orthat becomes water-containing following application to the skin ormucosal tissue.

[0022] In describing molecular structures and formulae herein, thephrase “having the formula” or “having the structure” is not intended tobe limiting and is used in the same way that the term “comprising” iscommonly used.

[0023] The term “alkyl” as used herein refers to a branched orunbranched saturated hydrocarbon group typically although notnecessarily containing 1 to about 24 carbon atoms, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl,and the like, as well as cycloalkyl groups such as cyclopentyl,cyclohexyl, and the like. Generally, although again not necessarily,alkyl groups herein contain 1 to about 12 carbon atoms. The term “loweralkyl” intends an alkyl group of one to six carbon atoms, preferably oneto four carbon atoms. “Substituted alkyl” refers to alkyl substitutedwith one or more substituent groups, and the terms“heteroatom-containing alkyl” and “heteroalkyl” refer to alkyl in whichat least one carbon atom is replaced with a heteroatom. If not otherwiseindicated, the terms “alkyl” and “lower alkyl” include linear, branched,cyclic, unsubstituted, substituted, and/or heteroatom-containing alkylor lower alkyl.

[0024] The term “alkenyl” as used herein refers to a branched orunbranched hydrocarbon group typically although not necessarilycontaining 2 to about 24 carbon atoms and at least one double bond, suchas ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl,decenyl, and the like. Generally, although again not necessarily,alkenyl groups herein contain 2 to about 12 carbon atoms. The term“lower alkenyl” intends an alkenyl group of two to six carbon atoms,preferably two to four carbon atoms. “Substituted alkenyl” refers toalkenyl substituted with one or more substituent groups, and the terms“heteroatom-containing alkenyl” and “heteroalkenyl” refer to alkenyl inwhich at least one carbon atom is replaced with a heteroatom.

[0025] The term “aryl” as used herein, and unless otherwise specified,refers to an aromatic substituent containing a single aromatic ring ormultiple aromatic rings that are fused together, linked covalently, orlinked to a common group such as a methylene or ethylene moiety. Thecommon linking group may also be a carbonyl as in benzophenone, anoxygen atom as in diphenylether, or a nitrogen atom as in diphenylamine.Preferred aryl groups contain one aromatic ring and are referred to as“monocyclic aryl.” “Substituted aryl” refers to an aryl moietysubstituted with one or more substituent groups, and the terms“heteroatom-containing aryl” and “heteroaryl” refer to aryl in which atleast one carbon atom is replaced with a heteroatom.

[0026] The term “heteroatom-containing” as in a “heteroatom-containinghydrocarbyl group” refers to a molecule or molecular fragment in whichone or more carbon atoms is replaced with an atom other than carbon,e.g., nitrogen, oxygen, sulfur, phosphorus, or silicon. Similarly, theterm “heteroalkyl” refers to an alkyl substituent that isheteroatom-containing, the term “heterocyclic” refers to a cyclicsubstituent that is heteroatom-containing, the term “heteroaryl” refersto an aryl substituent that is heteroatom-containing, and the like. Whenthe term “heteroatom-containing” appears prior to a list of possibleheteroatom-containing groups, it is intended that the term apply toevery member of that group. That is, the phrase “heteroatom-containingalkyl, alkenyl, and alkynyl” is to be interpreted as“heteroatom-containing alkyl, heteroatom-containing alkenyl, andheteroatom-containing alkynyl.”

[0027] By “substituted” as in “substituted alkyl,” “substitutedalkenyl,” “substituted aryl,” and the like, as alluded to in some of theaforementioned definitions, is meant that in the alkyl, alkenyl, aryl,or other moiety, at least one hydrogen atom bound to a carbon atom isreplaced with one or more substituents that are functional groups suchas hydroxyl, alkoxy, thio, amino, halo, and the like.

[0028] The terms “alkyl,” “alkenyl,” “aryl,” and the like are, unlessotherwise indicated, intended to include unsubstituted, substituted,heteroatom-containing, and substituted heteroatom-containing alkyl,alkenyl and aryl substituents.

[0029] II. Indications

[0030] The invention pertains to a skin lightening treatment of anindividual predisposed to or afflicted with hyperpigmentation,comprising topically administering to the affected skin area apharmaceutical formulation that consists essentially of apharmacologically active base, at least one pharmaceutically acceptabletopical carrier, and optionally at least one excipient. Active agents inaddition to the pharmacologically active base are unnecessary, as thebase is itself quite effective in achieving skin lightening. Preferably,the base is present at a concentration to provide the formulation with apH in the range of about 7.5 to about 13.0, more preferably about 8.0 to11.5, and most preferably about 8.5 to 10.5. In some aspects, the pHwill be in the range of about 9.5 to 11.5, preferably 10.0 to about11.5. In addition, or alternatively, the base is present at aconcentration effective to provide a pH on the skin surface in theaforementioned ranges, following topical application of the formulation.The term “hyperpigmentation” includes a range of skin disorders,including, but not limited to, regional hyperpigmentations bymelanocytic hyperactivity, such as idiopathic melasma arising duringpregnancy (“mask of pregnancy” or “chloasma”) or as a consequence ofoestrone/progestogen contraception; other localized hyperpigmentationsby benign melanocytic hyperactivity and proliferation, such as senilepigmental blemishes; disease-related hyperpigmentation; accidentalhyperpigmentations such as those due to photosensitization, geneticmakeup, chemical ingestion or other exposure, age, and post-lesionalscarring.

[0031] In a preferred embodiment, the hyperpigmentation that the methodand formulation of the invention are used to treat is localizedhyperpigmentation by benign melanocytic hyperactivity and proliferation,such as senile pigmental blemishes, also known as age spots. In aparticularly preferred embodiment, the invention is used to treat agespots. As is well known, age spots are common among the elderly; theyresult from age-related, localized melanocytic hyperactivity.

[0032] In another preferred embodiment, the hyperpigmentation treated isa regional hyperpigmentation such as, for example, idiopathic melasmaarising during pregnancy or as a consequence of oestrone/progestogencontraception.

[0033] In a further preferred embodiment, the hyperpigmentation that themethod and formulation of the invention are used to treat is anaccidental hyperpigmentation, e.g., a melanin disorder such ashyperpigmentation due to photosensitivity, hyperpigmentation due togenetic makeup, berloque dermatitis (resulting from exposure to oil ofbergamot, specifically the bergapten, or 5-methoxypsoralens, containedtherein), argyria (resulting from exposure to silver salts), orpost-lesional scarring.

[0034] III. The Pharmacologically Active Base

[0035] The pharmacologically active base of the invention is aninorganic or an organic pharmaceutically acceptable base. Preferredinorganic bases include inorganic hydroxides, inorganic oxides,inorganic salts of weak acids, and combinations thereof. Preferredorganic bases are nitrogenous bases.

[0036] It has long been thought that strong bases, such as NaOH, werenot suitable as pharmacologically active bases because they would damageskin. It has been now been discovered that the skin permeability ofvarious drugs could be enhanced without skin damage by exposing the skinto a base or basic solution, in a skin contacting formulation or patch.The desired pH of the solution on the skin can be obtained using avariety of bases or base concentrations. Accordingly, the pH is selectedso as to be low enough so as to not cause skin damage, but high enoughto enhance skin permeation to various active agents. As such, it isimportant that the amount of base in any patch or formulation isoptimized so as to increase the flux of the drug through the bodysurface while minimizing any possibility of skin damage. In general,this means that the pH at the body surface in contact with a formulationor drug delivery system of the invention is preferably in the range ofapproximately 8.0 to 13.0, preferably about 8.0 to 11.5, more preferablyabout 8.5 to 11.5 and most preferably about 8.5 to 10.5. In someaspects, the pH will be in the range of about 9.5 to 11.5, preferably10.0 to about 11.5.

[0037] In one preferred embodiment, the pH at the body surface is theprimary design consideration, i.e., the composition or system isdesigned so as to provide the desired pH at the body surface. Anhydrousformulations and transdermal systems may not have a measurable pH, andthe formulation or system can be designed so as to provide a target pHat the body surface. Moisture from the body surface can migrate into theformulation or system, dissolve the base and thus release the base intosolution, which will then provide the desired target pH at the skin'ssurface. In those instances, a hydrophilic composition is preferred. Inaddition, when using aqueous formulations, the pH of the formulation maychange over time after it is applied on the skin. For example, gels,solutions, ointments, etc., may experience a net loss of moisture afterbeing applied to the body surface, i.e., the amount of water lost isgreater than the amount of water received from the body surface. In thatcase, the pH of the formulation may be different than its pH whenmanufactured. This problem can be easily remedied by designing theaqueous formulations to provide a target pH at the skin's surface.

[0038] In other embodiments of the invention, the pH of the formulationor the drug composition contained within a delivery system will be inthe range of approximately 8.0 to 13.0, preferably about 8.0 to 11.5,more preferably about 8.5 to 11.5, and most preferably about 8.5 to10.5. In some aspects, the pH will be in the range of about 9.5 to 11.5,preferably 10.0 to 11.5. In one embodiment of the invention the pH ofthe formulation is higher than the pH at the body surface. For example,if an aqueous formulation is used, moisture from the body surface candilute the formulation, and thus provide for a different pH at the bodysurface, which will typically be lower than that of the formulationitself.

[0039] In one preferred embodiment, the body surface is exposed to abase or basic solution for a sufficient period of time so as to providea high pH at the body surface, thus creating channels in the skin ormucosa for the drug to go through. It is expected that drug flux isproportional to the strength of the solution and the duration ofexposure. However, it is desirable to balance the maximization of drugflux with the minimization of skin damage. This can be done in numerousways. For example, the skin damage may be minimized by selecting a lowerpH within the 8.0-13.0 range, by exposing the skin to the formulation orsystem for a shorter period of time, or by including at least oneirritation-mitigating additive. Alternatively, the patient can beadvised to change the location of application with each subsequentadministration.

[0040] While certain preferred amounts are set forth below, it isunderstood that, for all of the inorganic and organic bases describedherein, the optimum amount of any such base will depend on the strengthor weakness of the base and its molecular weight, and other factors suchas the number of ionizable sites in the active agent being administeredand whether there are any acidic species present in the formulation orpatch. One skilled in the art may readily determine the optimum amountfor any particular base such that the degree of enhancement is optimizedwhile the possibility of damage to the body surface is eliminated or atleast substantially minimized.

[0041] Inorganic Base

[0042] Exemplary inorganic bases are inorganic hydroxides, inorganicoxides, inorganic salts of weak acids, and combinations thereof.Preferred inorganic bases are those whose aqueous solutions have a highpH, and are acceptable as food or pharmaceutical additives. Examples ofsuch preferred inorganic bases are those listed below, along with theirrespective pHs. Some of the bases are identified by their hydrate forms,and it is understood that when referring to a “base”, both the hydratedand non-hydrated forms are intended to be included. Inorganic base pH ofAqueous Solution (concentration) Ammonium hydroxide^(1,2,3) 11.27 (1 N),10.27 (0.001 N) Sodium hydroxide^(1,2,3) 14 (5%), 13 (0.5%), 12 (0.05%)Potassium hydroxide^(1,2,3) 13.5 (0.1 M) Calcium hydroxide^(1,3) 12.4(saturated solution in water) Magnesium hydroxide^(1,3) 9.5 to 10.5slurry Magnesium oxide^(1,2,3) 10.3 (saturated aqueous solution) Calciumoxide³ Soluble in water, Form Ca(OH)₂ Sodium acetate^(1,3) ˜8.9 (0.1 N)Sodium acetate, trihydrate^(1,2) 8.9 (0.1 N) Sodium acetate,anhydrous^(1,2) ˜8.9 (0.1 N) Sodium borate decahydrate^(1,2) ˜8.8-9.4,9.15 to 9.2 (0.01 M) Sodium borate^(1,2,3) 8.8-9.4, 9.15 to 9.2 (0.01 M)Sodium metaborate Strongly alkaline Sodium carbonate^(1,2,3) ˜11.6Sodium carbonate hydrate¹ ˜11.6 Sodium carbonate anhydrous ˜11.6 Sodiumbicarbonate^(1,2,3) 8.3 (0.1 M fresh) Sodium phosphate, tribasic^(1,3)˜11.5 (0.1%), ˜11.7 (0.5%), ˜11.9 (1.0%) Sodium phosphate, tribasic 11.5(0.1%), 11.7 (0.5%), 11.9 (1.0%) dodecahydrate Sodium phosphate,dibasic, 9.1 (1%) anhydrous^(1,2) Sodium phosphate, dibasic, ˜9.5heptahydrate^(1,2) Sodium phosphate, dibasic^(1,3) ˜9.5 Sodiumphosphate, dibasic, ˜9.5 dihydrate¹ Sodium phosphate, dibasic, ˜9.5dodecahydrate Potassium carbonate^(1,3) ˜11.6 Potassiumbicarbonate^(1,3) 8.2 (0.1 M) Potassium citrate^(1,2,3) ˜8.5 Potassiumcitrate mono- ˜8.5 hydrate Potassium acetate^(1,3) 9.7 (0.1 M) Potassiumphosphate, Aqueous solution is slightly alkaline dibasic^(1,2) Potassiumphosphate, tribasic³ Aqueous solution is strongly alkaline Ammoniumphosphate, ˜8 dibasic^(1,2,3)

Inorganic Hydroxides

[0043] Inorganic hydroxides include, for example, ammonium hydroxide,alkali metal hydroxide and alkaline earth metal hydroxides, and mixturesthereof. Preferred inorganic hydroxides include ammonium hydroxide;monovalent alkali metal hydroxides such as sodium hydroxide andpotassium hydroxide; divalent alkali earth metal hydroxides such ascalcium hydroxide and magnesium hydroxide; and combinations thereof.

[0044] The amount of inorganic hydroxide included in the compositionsand systems of the invention, will typically represent about 0.3-7.0 wt%, preferably 0.5-4.0 wt %, more preferably about 0.5-3.0 wt %, mostpreferably about 0.75-2.0 wt %, of a topically applied formulation or ofa drug reservoir of a drug delivery system, or patch.

[0045] The aforementioned amounts are particularly applicable to thoseformulations and patches in which the active agent is (1) an unchargedmolecule, e.g., wherein a basic drug is in nonionized, free-base form,(2) a basic salt of an acidic drug, or (3) there are no additionalspecies in the formulation or patch that could react with or beneutralized by the inorganic hydroxide, to any significant degree.

[0046] For formulations and patches in which the drug is in the form ofan acid addition salt, and/or wherein there are additional species inthe formulations or systems that can be neutralized by or react with theinorganic base (i.e., acidic inactive ingredients), the amount ofinorganic hydroxide is preferably the total of (1) the amount necessaryto neutralize the acid addition salt and/or other base-neutralizablespecies (i.e., the “acidic species”), plus (2) about 0.3-7.0 wt %,preferably 0.5-4.0 wt %, more preferably about 0.5-3.0 wt %, mostpreferably about 0.75-2.0 wt %, of the formulation or drug reservoir.That is, for an acid addition salt, the enhancer is preferably presentin an amount just sufficient to neutralize the salt, plus an additionalamount (i.e., about 0.3-7.0 wt %, preferably 0.5-4.0 wt %, morepreferably about 0.5-3.0 wt %, most preferably about 0.75-2.0 wt %) toenhance the flux of the drug through the skin or mucosal tissue. Basicdrugs in the form of a neutral, free base or basic salt of acidic drugare usually not affected by a base, and thus for these drugs, the amountin (1) is usually the amount necessary to neutralize inactive componentsthat are acidic. For patches, the aforementioned percentages are givenrelative to the total weight of the formulation components and theadhesive, gel or liquid reservoir.

[0047] Still greater amounts of inorganic hydroxide may be used bycontrolling the rate and/or quantity of release of the base, preferablyduring the drug delivery period itself.

Inorganic Oxides

[0048] Inorganic oxides include, for example, magnesium oxide, calciumoxide, and the like.

[0049] The amount of inorganic oxide included in the compositions andsystems of the invention may be substantially higher than the numbersset forth above for the inorganic hydroxide, and may be as high as 20 wt%, in some cases as high as 25 wt % or higher, but will generally be inthe range of about 2-20 wt %. These amounts may be adjusted to take intoconsideration the presence of any base-neutralizable species.

Inorganic Salts of Weak Acids

[0050] Inorganic salts of weak acids include, ammonium phosphate(dibasic); alkali metal salts of weak acids such as sodium acetate,sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate,sodium phosphate (tribasic), sodium phosphate (dibasic), potassiumcarbonate, potassium bicarbonate, potassium citrate, potassium acetate,potassium phosphate (dibasic), potassium phosphate (tribasic); alkalineearth metal salts of weak acids such as magnesium phosphate and calciumphosphate; and the like, and combinations thereof.

[0051] Preferred inorganic salts of weak acids include, ammoniumphosphate (dibasic) and alkali metal salts of weak acids.

[0052] The amount of inorganic salts of weak acids included in thecompositions and systems of the invention may be substantially higherthan the numbers set forth above for the inorganic hydroxide, and may beas high as 20 wt %, in some cases as high as 25 wt % or higher, but willgenerally be in the range of approximately 2-20 wt %. These amounts maybe adjusted to take into consideration the presence of anybase-neutralizable species.

[0053] Organic Bases

[0054] Organic bases suitable for use in the invention are compoundshaving an amino group, amido group, an oxime, a cyano group, an aromaticor non-aromatic nitrogen-containing heterocycle, a urea group, andcombinations thereof. More specifically, examples of suitable organicbases are nitrogenous bases, which include, but are not limited to,primary amines, secondary amines, tertiary amines, amides, oximes, cyano(—CN) containing groups, aromatic and non-aromatic nitrogen-containingheterocycles, urea, and mixtures thereof. Preferred organic bases areprimary amines, secondary amines, tertiary amines, aromatic andnon-aromatic nitrogen-containing heterocycles, and mixtures thereof.

[0055] For nitrogenous bases, the amount of the agent will typicallyrepresent about 0.5-4.0 wt %, preferably about 0.5-3.0 wt %, morepreferably about 0.75-2.0 wt %, of a topically applied formulation or ofa drug reservoir of a drug delivery system or a patch. These amounts maybe adjusted to take into consideration the presence of anybase-neutralizable species.

[0056] Still greater amounts of the nitrogenous base may be useddepending on the strength of the base and the rate and/or quantity ofrelease of the nitrogenous base preferably during the drug deliveryperiod itself.

[0057] Preferred organic bases are those whose aqueous solutions have ahigh pH or a high pKa (more preferably a pKa>9), and are acceptable asfood or pharmaceutical additives. Examples of such preferred organicbases are those listed below, along with their respective pHs (or pKavalues). pH of Aqueous Organic base Solution (concentration)2-amino-2-methyl-1,3-propanediol¹ 10.8 (0.1 m)2-amino-2-methyl-1-propanol¹ 11.3 (0.1 m) Diethanolamine¹ 11.0 (0.1 N)Triethanolamine¹ 10.5 (0.1 N) Butylamine² pKa = 10.56 Dimethylamine²Strong base, pKa = 10.73 Cyclohexylamine² Strong base, pKa = 10.64Ethylenediamine² Strong base, pKa = 10.71 Isopentylamine² pKa = 10.6Monoethanolamine² 12.1 (25%), 12.05 (0.1 N), pKa = 9.4 Phenethylamine²Strong base, pKa = 9.83 Piperidine² Strong base, pKa = 11.12Pyrrolidine² Strong base, pKa = 11.27 Trimethylamine² Strong base, pKa =9.81

Amines

[0058] Suitable nitrogenous bases may contain any one or a combinationof the following:

[0059] primary amino (—NH₂) groups;

[0060] mono-substituted (secondary) amino groups —NHR where R ishydrocarbyl, generally either alkyl or aryl, e.g., lower alkyl orphenyl, and may be substituted with one or more nonhydrocarbylsubstituents, e.g., 1 to 3 halo, hydroxyl, thiol, or lower alkoxy groups(such -NHR groups include, for example, methylamino, ethylamino,isopropylamino, butylamino, cyclopropylamino, cyclohexylamino,n-hexylamino, phenylamino, benzylamino, chloroethylamino,hydroxyethylamino, etc.);

[0061] di-substituted (tertiary) amino groups —NR^(a)R^(b) where R^(a)and R^(b) may be the same or different and are as defined above for R(suitable —NR^(a)R^(b) include, for example, dimethylamino,diethylamino, diisopropylamino, dibutylamino, methylpropylamino,methylhexylamino, methylcyclohexylamino, ethylcyclopropylamino,ethylchloroethylamino, methylbenzylamino, methylphenylamino,methyltoluylamino, methyl-p-chlorophenylamino, methylcyclohexylamino,etc.);

[0062] amides —(CO)—NR^(c)R^(d) where R^(c) and R^(d) may be the same ordifferent and are either hydrogen or R, wherein R is as defined above(including, for example, amides wherein one of R^(c) and R^(d) is H andthe other is methyl, butyl, benzyl, etc.);

[0063] cyano (—CN);

[0064] aromatic nitrogen-containing heterocycles, typically five- orsix-membered monocyclic substituents, or bicyclic fused or linked five-or six-membered rings (such as pyrrolyl, pyrrolidinyl, pyridinyl,quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl,tetrazolyl, etc.); and

[0065] non-aromatic nitrogen-containing heterocycles, typically four- tosix-membered rings, including lactams and imides, e.g., pyrrolidino,morpholino, piperazino, piperidino, N-phenyl—propiolactam,-butyrolactam, -caprolactam, acetimide, phthalimide, succinimide, etc.

[0066] Primary amines, secondary amines, and tertiary amines may begenerically grouped as encompassed by the molecular structure NR¹R²R³wherein R¹, R² and R³ are selected from H, alkyl, hydroxyalkyl,alkoxyalkyl, alkenyl, hydroxyalkenyl, alkoxyalkenyl, cycloalkyl,cycloalkyl-substituted alkyl, monocyclic aryl, and monocyclicaryl-substituted alkyl, with the proviso that at least one of R¹, R² andR³ is other than H. Examples of such amines include, without limitation,diethanolamine, triethanolamine, isopropanolamine, triisopropanolamine,dibutanol amine, tributanol amine, N-dodecylethanolamine,N-(2-methoxyethyl) dodecylamine, N-(2,2-dimethoxyethyl)dodecylamine,N-ethyl-N-(dodecyl)ethanolamine, N-ethyl-N-(2-methoxyethyl)dodecylamine,N-ethyl-N-(2,2-dimethoxyethyl) dodecylamine,dimethyldodecylamine-N-oxide, monolauroyl lysine, dipalmitoyl lysine,dodecylamine, stearylamine, phenylethylamine, triethylamine, PEG-2oleamine, PEG-5 oleamine, dodecyl 2-(N,N-dimethylamino)propionate,bis(2-hydroxyethyl)oleylamine, and combinations thereof.

[0067] Exemplary primary amines include 2-aminoethanol, 2-aminoheptane,2-amino-2-methyl-1,3 propanediol, 2-amino-2-methyl-1-propanol,n-amylamine, benzylamine, 1 ,4-butanediamine, n-butylamine,cyclohexylamine, ethylamine, ethylenediamine, methylamine,α-methylbenzylamine, phenethylamine, propylamine, andtris(hydroxymethyl)aminomethane.

[0068] Exemplary secondary amines include compounds that contain groupssuch as methylamino, ethylamino, isopropylamino, butylamino,cyclopropylamino, cyclohexylamino, n-hexylamino, phenylamino,benzylamino, chloroethylamino, hydroxyethylamino, and so forth.Exemplary secondary amines include diethanolamine, diethylamine,diisopropylamine, and dimethylamine.

[0069] Exemplary tertiary amines include compounds that contain groupssuch as dibutylamino, diethylamino, dimethylamino, diisopropylamino,ethylchloroethylamino, ethylcyclopropylamino, methylhexylamino,methylcyclohexylamino, methylpropylamino, methylbenzylamino,methyl-p-chlorophenylamino, methylcyclohexylamino, methylphenylamino,methyltoluylamino, and so forth. Exemplary tertiary amines includeN,N-diethylaniline, N,N-dimethylglycine, triethanolamine, triethylamine,and trimethylamine.

Amides

[0070] Amides, as will be appreciated by those skilled in the art, havethe molecular structure R⁴—(CO)—NR⁵R⁶ where R⁴, R⁵ and R⁶ are generallyselected from H, alkyl, cycloalkyl, cycloalkyl-substituted alkyl,monocyclic aryl, and monocyclic aryl-substituted alkyl. Examples ofsuitable amides herein include, without limitation,hexamethyleneacetamide, hexamethyleneoctamide, hexamethylene lauramide,hexamethylene palmitamide, N,N-dimethyl formamide, N,N-dimethylacetamide, N,N-dimethyloctamide, N,N-dimethyldecamide, toluamide,dimethyl-m-toluamide, diethyl-m-toluamide, and combinations thereof.

Nitrogen-Containing Heterocycles

[0071] Nitrogen-containing heterocycles suitable as thepharmacologically active base herein include, by way of example,2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone,1-propyl-3-dodecylpyrrolidine, 1-dodecyclazacycloheptan-2-one, ethylenethiourea, hydantoin, oxalylurea, imidazolidilyl urea, N-octadecylmorpholine, dodecylpyridinium, N-dodecylpyrrolidine,N-dodecylpiperidine, N-dodecylhomopiperidine, and combinations thereof.

[0072] Aromatic nitrogen-containing heterocycles, typically contain a 5-or 6-membered monocyclic substituent, or a bicyclic fused or linked 5-or 6-membered ring, such as imidazolyl, indolyl, pyridinyl, pyrimidinyl,pyrrolyl, quinolinyl, tetrazolyl, 1,2,4-triazolyl, etc.

[0073] Aromatic nitrogen-containing heterocycles suitable as the organicbase herein include, by way of example, 2-amino-pyridine, benzimidazole,2,5-diaminopyridine, 2,4-dimethylimidazole, 2,3-dimethylpyridine,2,4-dimethylpyridine, 3,5-dimethylpyridine, imidazole, methoxypyridine,γ-picoline, 2,4,6-trimethylpyridine, and combinations thereof.

[0074] Non-aromatic nitrogen-containing heterocycles, typically contain4- to 6-membered rings such as acetimido, morpholinyl, lactams andimides (e.g., -butyrolactam, -caprolactam, N-phenyl—propiolactam),phthalimido, piperidyl, piperidino, piperazinyl, pyrrolidinyl,succinimido, etc.

[0075] Non-aromatic nitrogen-containing heterocycles include, by way ofexample, 1,2-dimethylpiperidine, 2,5-dimethylpiperazine,1,2-dimethylpyrrolidine, 1-ethylpiperidine, n-methylpyrrolidine,morpholine, piperazine, piperidine, pyrrolidine,2,2,6,6-tetramethylpiperidine, 2,2,4-trimethylpiperidine, andcombinations thereof.

[0076] For all pharmacologically active bases herein, the optimum amountof any particular agent will depend on the strength or weakness of thebase, the molecular weight of the base, and other factors such as thenumber of ionizable sites in the drug administered and any other acidicspecies in the formulation or patch. One skilled in the art may readilydetermine the optimum amount for any particular agent by ensuring that aformulation is effective to provide a pH at the skin surface, uponapplication of the formulation, in the range of about 7.5 to about 13.0,preferably about 8.0 to about 11.5, preferably in the range of about 8.5to about 10.5. This in turn ensures that the degree of treatment ismaximized while the possibility of damage to the body surface iseliminated or at least substantially minimized.

[0077] IV. Pharmaceutical Formulations and Skin Patches

[0078] The pharmaceutical formulation of the invention comprises apharmaceutically acceptable topical carrier and an active agent thatconsists essentially of a pharmacologically active base. Thepharmacologically active base is present at a concentration sufficientto provide a formulation pH in the range of approximately 7.5 to 13.0,preferably 8.0 to 11.5, and most preferably 8.5 to 10.5. The formulationmay be in any form suitable for application to the body surface, and maycomprise, for example, a cream, lotion, solution, gel, ointment, paste,or the like, and/or may be prepared so as to contain liposomes,micelles, and/or microspheres. For those formulations in which thepharmacologically active base is a hydroxide-releasing agent, it ispreferred although not essential that water be present. Thus, such aformulation may be aqueous, i.e., contain water, or may be nonaqueousand optionally used in combination with an occlusive overlayer so thatmoisture evaporating from the body surface is maintained within theformulation upon application to the body surface and thereafter.

[0079] Ointments, as is well known in the art of pharmaceuticalformulation, are semisolid preparations that are typically based onpetrolatum or other petroleum derivatives. The specific ointment base tobe used, as will be appreciated by those skilled in the art, is one thatwill provide for optimum drug delivery, and, preferably, will providefor other desired characteristics as well, e.g., emolliency or the like.As with other carriers or vehicles, an ointment base should be inert,stable, nonirritating and nonsensitizing. As explained in Remington: TheScience and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack PublishingCo., 1995), at pages 1399-1404, ointment bases may be grouped in fourclasses: oleaginous bases; emulsifiable bases; emulsion bases; andwater-soluble bases. Oleaginous ointment bases include, for example,vegetable oils, fats obtained from animals, and semisolid hydrocarbonsobtained from petroleum. Emulsifiable ointment bases, also known asabsorbent ointment bases, contain little or no water and include, forexample, hydroxystearin sulfate, anhydrous lanolin, and hydrophilicpetrolatum. Emulsion ointment bases are either water-in-oil (W/O)emulsions or oil-in-water (O/W) emulsions, and include, for example,cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid.Preferred water-soluble ointment bases are prepared from polyethyleneglycols of varying molecular weight; again, see Remington: The Scienceand Practice of Pharmacy for further information.

[0080] Creams, as also well known in the art, are viscous liquids orsemisolid emulsions, either oil-in-water or water-in-oil. Cream basesare water-washable, and contain an oil phase, an emulsifier, and anaqueous phase. The oil phase, also called the “internal” phase, isgenerally comprised of petrolatum and a fatty alcohol such as cetyl orstearyl alcohol. The aqueous phase usually, although not necessarily,exceeds the oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic, or amphoteric surfactant.

[0081] As will be appreciated by those working in the field ofpharmaceutical formulation, gels are semisolid, suspension-type systems.Single-phase gels contain organic macromolecules distributedsubstantially uniformly throughout the carrier liquid, which istypically aqueous, but also, preferably, contains an alcohol and,optionally, an oil. Preferred “organic macromolecules,” i.e., gellingagents, are crosslinked acrylic acid polymers such as the “carbomer”family of polymers, e.g., carboxypolyalkylenes that may be obtainedcommercially under the Carbopol® trademark. Also preferred arehydrophilic polymers such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol;cellulosic polymers such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, and methyl cellulose; gums such as tragacanth and xanthangum; sodium alginate; and gelatin. In order to prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing orstirring, or combinations thereof.

[0082] Lotions, which are preferred for the delivery of cosmetic agents,are preparations to be applied to the skin surface without friction, andare typically liquid or semiliquid preparations in which solidparticles, including the active agent, are present in a water or alcoholbase. Lotions are usually suspensions of solids, and preferably, for thepresent purpose, comprise a liquid oily emulsion of the oil-in-watertype. Lotions are preferred formulations herein for treating large bodyareas, because of the ease of applying a more fluid composition. It isgenerally necessary that the insoluble matter in a lotion be finelydivided. Lotions will typically contain suspending agents to producebetter dispersions as well as compounds useful for localizing andholding the active agent in contact with the skin, e.g.,methylcellulose, sodium carboxymethyl-cellulose, or the like.

[0083] Pastes are semisolid dosage forms in which the active agent issuspended in a suitable base. Depending on the nature of the base,pastes are divided between fatty pastes or those made from single-phaseaqueous gels. The base in a fatty paste is generally petrolatum,hydrophilic petrolatum, or the like. The pastes made from single-phaseaqueous gels generally incorporate carboxymethylcellulose or the like asa base.

[0084] Formulations may also be prepared with liposomes, micelles, andmicrospheres. Liposomes are microscopic vesicles having a lipid wallcomprising a lipid bilayer, and can be used as drug delivery systemsherein as well. Generally, liposome formulations are preferred forpoorly soluble or insoluble pharmaceutical agents. Liposomalpreparations for use in the instant invention include cationic(positively charged), anionic (negatively charged), and neutralpreparations. Cationic liposomes are readily available. For example,N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes areavailable under the tradename Lipofectin® (GIBCO BRL, Grand Island,N.Y.). Similarly, anionic and neutral liposomes are readily available aswell, e.g., from Avanti Polar Lipids (Birmingham, Ala.), or can beeasily prepared using readily available materials. Such materialsinclude phosphatidyl choline, cholesterol, phosphatidyl ethanolamine,dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol(DOPG), and dioleoylphoshatidyl ethanolamine (DOPE), among others. Thesematerials can also be mixed with DOTMA in appropriate ratios. Methodsfor making liposomes using these materials are well known in the art.

[0085] Micelles are known in the art as comprised of surfactantmolecules arranged so that their polar headgroups form an outerspherical shell, while the hydrophobic hydrocarbon chains are orientedtowards the center of the sphere, forming a core. Micelles form in anaqueous solution containing surfactant at a high enough concentration sothat micelles naturally result. Surfactants useful for forming micellesinclude, but are not limited to, potassium laurate, sodium octanesulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodiumlauryl sulfate, docusate sodium, decyltrimethylammonium bromide,dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,tetradecyltrimethylammonium chloride, dodecylammonium chloride, polyoxyl8 dodecyl ether, polyoxyl 12 dodecyl ether, nonoxynol 10, and nonoxynol30. Micelle formulations can be used in conjunction with the presentinvention either by incorporation into the reservoir of a topical ortransdermal delivery system, or into a formulation to be applied to thebody surface.

[0086] Microspheres, similarly, may be incorporated into the presentformulations and drug delivery systems. Like liposomes and micelles,microspheres essentially encapsulate a drug or drug-containingformulation. Microspheres are generally, although not necessarily,formed from synthetic or naturally occurring biocompatible polymers, butmay also be comprised of charged lipids such as phospholipids.Preparation of microspheres is well known in the art and described inthe pertinent texts and literature.

[0087] Various additives, known to those skilled in the art, may beincluded in the topical formulations. For example, solvents, includingrelatively small amounts of alcohol, may be used to solubilize certainformulation components. Although the pharmacologically active basesherein do penetrate into the skin and have in fact been described asskin permeation enhancers, it may be desirable, with weaker bases orparticularly severe dermatoses, to include an added permeation enhancerin the formulation. Examples of suitable enhancers include, but are notlimited to, ethers such as diethylene glycol monoethyl ether (availablecommercially as Transcutol®) and diethylene glycol monomethyl ether;surfactants such as sodium laurate, sodium lauryl sulfate,cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231,182, 184), Tween (20, 40, 60, 80) and lecithin (U.S. Pat. No.4,783,450); alcohols such as ethanol, propanol, octanol, benzyl alcohol,and the like; polyethylene glycol and esters thereof such aspolyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No.4,568,343); amides and other nitrogenous compounds such as urea,dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone,1-methyl-2-pyrrolidone, ethanolamine, diethanolamine andtriethanolamine; terpenes; alkanones; and organic acids, particularlycitric acid and succinic acid. Azone and sulfoxides such as DMSO andC₁₀MSO may also be used, but are less preferred.

[0088] Most preferred enhancers are those lipophilic co-enhancerstypically referred to as “plasticizing” enhancers, i.e., enhancers thathave a molecular weight in the range of about 150 to 1000, with anaqueous solubility of less than about 1 wt. %, preferably less thanabout 0.5 wt. %, and most preferably less than about 0.2 wt. %. TheHildebrand solubility parameter of plasticizing enhancers is in therange of about 2.5 to about 10, preferably in the range of about 5 toabout 10. Such enhancers are described in detail in co-pending, commonlyassigned U.S. patent application Ser. No. 09/738,410, filed on Dec. 14,2000, and in International Patent Application No. PCT/US00/34483,published Jun. 21, 2001 as WO 01/43775 A2. Preferred lipophilicenhancers are fatty esters, fatty alcohols, and fatty ethers. Examplesof specific and most preferred fatty acid esters include methyl laurate,ethyl oleate, propylene glycol monolaurate, propylene glyceroldilaurate, glycerol monolaurate, glycerol monooleate, isopropyln-decanoate, and octyldodecyl myristate. Fatty alcohols include, forexample, stearyl alcohol and oleyl alcohol, while fatty ethers includecompounds wherein a diol or triol, preferably a C₂-C₄ alkane diol ortriol, are substituted with one or two fatty ether substituents.

[0089] Additional permeation enhancers will be known to those ofordinary skill in the art of topical drug delivery, and/or are describedin the pertinent texts and literature. See, e.g., PercutaneousPenetration Enhancers, Smith et al., editors (CRC Press, 1995).

[0090] The present formulations may also include conventional additivessuch as opacifiers, antioxidants, fragrance, colorant, gelling agents,thickening agents, stabilizers, surfactants, and the like. Other agentsmay also be added, such as antimicrobial agents to prevent spoilage uponstorage, i.e., to inhibit growth of microbes such as yeasts and molds.Suitable antimicrobial agents are typically selected from the groupconsisting of the methyl and propyl esters of p-hydroxybenzoic acid(i.e., methyl and propyl paraben), sodium benzoate, sorbic acid,imidurea, and combinations thereof.

[0091] The formulations may also contain irritation-mitigating additivesto minimize or eliminate the possibility of skin irritation or skindamage resulting from the pharmacologically active base or othercomponents of the composition. Suitable irritation-mitigating additivesinclude, for example: -tocopherol; monoamine oxidase inhibitors,particularly phenyl alcohols such as 2-phenyl-1-ethanol; glycerin;salicylic acids and salicylates; ascorbic acids and ascorbates;ionophores such as monensin; amphiphilic amines; ammonium chloride;N-acetylcysteine; cis-urocanic acid; capsaicin; and chloroquine. Theirritant-mitigating additive, if present, may be incorporated into thepresent formulations at a concentration effective to mitigate irritationor skin damage, typically representing not more than about 20 wt. %,more typically not more than about 5 wt. %, of the composition.

[0092] The pharmacologically active base may also be administeredthrough the skin or mucosal tissue using a conventional skin patch,wherein the agent is contained within a laminated structure that servesas a drug delivery device to be affixed to the body surface. In such astructure, the pharmaceutical formulation is contained in a layer, or“reservoir,” underlying an upper backing layer. The laminated structuremay contain a single reservoir, or it may contain multiple reservoirs.

[0093] In one embodiment, the reservoir comprises a polymeric matrix ofa pharmaceutically acceptable adhesive material that serves to affix thesystem to the skin during drug delivery; typically, the adhesivematerial is a pressure-sensitive adhesive (PSA) that is suitable forlong-term skin contact, and which should be physically and chemicallycompatible with the pharmacologically active base and any carriers,vehicles or other additives that are present. Examples of suitableadhesive materials include, but are not limited to, the following:polyethylenes; polysiloxanes; polyisobutylenes; polyacrylates;polyacrylamides; polyurethanes; plasticized ethylene-vinyl acetatecopolymers; and tacky rubbers such as polyisobutene, polybutadiene,polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, andneoprene (polychloroprene). Preferred adhesives are polyisobutylenes.

[0094] The backing layer functions as the primary structural element ofthe transdermal system and provides the device with flexibility and,preferably, occlusivity. The material used for the backing layer shouldbe inert and incapable of absorbing drug, pharmacologically active base,or components of the formulation contained within the device. Thebacking is preferably comprised of a flexible elastomeric material thatserves as a protective covering to prevent loss of drug and/or vehiclevia transmission through the upper surface of the patch, and willpreferably impart a degree of occlusivity to the system, such that thearea of the body surface covered by the patch becomes hydrated duringuse. The material used for the backing layer should permit the device tofollow the contours of the skin and be worn comfortably on areas of skinsuch as at joints or other points of flexure, which are normallysubjected to mechanical strain, with little or no likelihood of thedevice disengaging from the skin due to differences in the flexibilityor resiliency of the skin and the device. The materials used as thebacking layer are either occlusive or permeable, as noted above,although occlusive backings are preferred, and are generally derivedfrom synthetic polymers (e.g., polyester, polyethylene, polypropylene,polyurethane, polyvinylidine chloride, and polyether amide), naturalpolymers (e.g., cellulosic materials), or macroporous woven and nonwovenmaterials.

[0095] During storage and prior to use, the laminated structure includesa release liner. Immediately prior to use, this layer is removed fromthe device so that the system may be affixed to the skin. The releaseliner should be made from a drug/vehicle impermeable material, and is adisposable element that serves only to protect the device prior toapplication. Typically, the release liner is formed from a materialimpermeable to the pharmacologically active base, and which is easilystripped from the patch prior to use.

[0096] In an alternative embodiment, the active agent-containingreservoir and skin contact adhesive are present as separate and distinctlayers, with the adhesive underlying the reservoir. In such a case, thereservoir may be a polymeric matrix as described above. Alternatively,the reservoir may be comprised of a liquid or semisolid formulationcontained in a closed compartment or “pouch,” or it may be a hydrogelreservoir, or may take some other form. Hydrogel reservoirs areparticularly preferred herein. As will be appreciated by those skilledin the art, bydrogels are macromolecular networks that absorb water andthus swell but do not dissolve in water. That is, hydrogels containhydrophilic functional groups that provide for water absorption, but thehydrogels are comprised of crosslinked polymers that give rise toaqueous insolubility. Generally, then, hydrogels are comprised ofcrosslinked hydrophilic polymers such as a polyurethane, a polyvinylalcohol, a polyacrylic acid, a polyoxyethylene, a polyvinylpyrrolidone,a poly(hydroxyethyl methacrylate) (poly(HEMA)), or a copolymer ormixture thereof. Particularly preferred hydrophilic polymers arecopolymers of HEMA and polyvinylpyrrolidone.

[0097] Additional layers, e.g., intermediate fabric layers and/orrate-controlling membranes, may also be present in any of these drugdelivery systems. Fabric layers may be used to facilitate fabrication ofthe device, while a rate-controlling membrane may be used to control therate at which a component permeates out of the device. The component maybe an active agent, an enhancer, or some other component contained inthe drug delivery system. A rate-controlling membrane, if present, willbe included in the system on the skin side of one or more of the drugreservoirs. The materials used to form such a membrane are selected tolimit the flux of one or more components contained in the drugformulation. Representative materials useful for formingrate-controlling membranes include polyolefins such as polyethylene andpolypropylene, polyamides, polyesters, ethylene-ethacrylate copolymer,ethylene-vinyl acetate copolymer, ethylene-vinyl methylacetatecopolymer, ethylene-vinyl ethylacetate copolymer, ethylene-vinylpropylacetate copolymer, polyisoprene, polyacrylonitrile,ethylene-propylene copolymer, and the like.

[0098] Generally, the underlying surface of the transdermal device,i.e., the skin contact area, has an area in the range of about 5 cm² to200 cm², preferably 5 cm² to 100 cm², more preferably 20 cm² to 60 cm².That area will vary, of course, with the size of the skin area to betreated, the amount of drug to be delivered, and the flux of the drugthrough the body surface. Larger patches will be necessary toaccommodate larger treatment areas and larger quantities of activeagent, while smaller patches can be used for smaller treatment areas andsmaller quantities of active agent and/or for active agents that exhibita relatively high permeation rate.

[0099] Such drug delivery systems may be fabricated using conventionalcoating and laminating techniques known in the art. For example,adhesive matrix systems can be prepared by casting a fluid admixture ofadhesive, active agent, and vehicle onto the backing layer, followed bylamination of the release liner. Similarly, the adhesive mixture may becast onto the release liner, followed by lamination of the backinglayer. Alternatively, the drug reservoir may be prepared in the absenceof drug or excipient, and then loaded by “soaking” in a drug/vehiclemixture. In general, these patches are fabricated by solventevaporation, film casting, melt extrusion, thin film lamination, diecutting, or the like. The active agent will generally be incorporatedinto the device during patch manufacture rather than subsequent topreparation of the device.

[0100] In a preferred delivery system, an adhesive overlayer that alsoserves as a backing for the delivery system is used to better secure thepatch to the body surface. This overlayer is sized such that it extendsbeyond the drug reservoir so that adhesive on the overlayer comes intocontact with the body surface. The overlayer is useful because theadhesive/drug reservoir layer may lose its adhesion a few hours afterapplication due to hydration. By incorporating such adhesive overlayer,the delivery system remains in place for the required period of time.

[0101] Other types and configurations of topically applied drug deliverysystems may also be used in conjunction with the present invention, aswill be appreciated by those skilled in the art of topical andtransdermal drug delivery. See, for example, Ghosh, Transdermal andTopical Drug Delivery Systems (Interpharm Press, 1997), particularlyChapters 2 and 8.

[0102] V. Administration

[0103] The method of delivery of the active agent may vary, butnecessarily involves application of a formulation of the invention to anarea of body surface for which skin lightening is desired, such as areasof hyperpigmentation. A cream, ointment, or lotion may be spread on theaffected surface and gently rubbed in. A solution may be applied in thesame way, but more typically will be applied with a dropper, swab, orthe like, and carefully applied to the affected areas.

[0104] The dosage regimen will depend on a number of factors that mayreadily be determined, such as the severity of the hyperpigmentation andthe responsiveness of the condition to be treated, but will normally beone or more doses per day, with a course of treatment lasting fromseveral days to several months, or until a cure is effected or adiminution of pigmentation is achieved. One of ordinary skill mayreadily determine optimum dosages, dosing methodologies and repetitionrates. In general, it is contemplated that the formulation will beapplied one to four times daily. With a skin patch, the device isgenerally maintained in place on the body surface throughout a drugdelivery period, typically in the range of 8 to 72 hours, and replacedas necessary.

[0105] It is to be understood that while the invention has beendescribed in conjunction with the preferred specific embodimentsthereof, the foregoing description is intended to illustrate and notlimit the scope of the invention. Other aspects, advantages, andmodifications will be apparent to those skilled in the art to which theinvention pertains. Furthermore, the practice of the present inventionwill employ, unless otherwise indicated, conventional techniques of drugformulation, particularly topical and transdermal drug formulation,which are within the skill of the art. Such techniques are fullyexplained in the literature. See Remington: The Science and Practice ofPharmacy, cited supra, as well as Goodman & Gilman's The PharmacologicalBasis of Therapeutics, 9th edition (New York: McGraw-Hill, 1996).

[0106] All patents, patent applications, and publications mentionedherein are hereby incorporated by reference in their entireties.

Experimental

[0107] The practice of the present invention will employ, unlessotherwise indicated, conventional techniques of pharmaceuticalformulation and the like, which are within the skill of the art. Suchtechniques are fully explained in the literature. In the followingexamples, efforts have been made to ensure accuracy with respect tonumbers used (e.g., amounts, temperatures, etc.) but some experimentalerror and deviation should be accounted for. Unless otherwise indicated,temperature is in degrees Celsius and pressure is at or near atmosphericpressure at sea level. All reagents were obtained commercially unlessotherwise indicated.

EXAMPLE 1

[0108] A topical gel of the invention is prepared by conventionalpharmaceutical methods. The indicated amounts of the followingingredients are used: Ingredient Amount Purified water 600 gramsPolyethylene glycol 400 grams Potassium hydroxide 0.01 gram Edetatedisodium 0.1 gram Carbomer 934P 12.5 grams Poloxamer 407 2.0 gramsPolysorbate 40 2.0 grams Butylated hydroxytoluene 0.5 grams Benzylalcohol 10.0 grams

[0109] The carbomer 934P and the edetate disodium are added to 250 mL ofthe purified water, and the mixture is homogenized at low speed untilthe carbomer is dispersed. Next, the polaxamer 407, mixed with 250 mL ofthe purified water, is added to the carbomer mixture, and the resultingmixture is homogenized at low speed. The potassium hydroxide, dissolvedin 100 mL of purified water, is added to this mixture, and the resultingmixture (Mixture 1) is homogenized at low speed. In a separatecontainer, the polysorbate 40 and the butylated hydroxytoluene are addedto the polyethylene glycol, and the resulting mixture is heated to 65°C. and maintained at this temperature until all the compounds aredissolved; this mixture is then allowed to cool to room temperature, atwhich time the benzyl alcohol is added, and the resulting mixture ishomogenized at low speed. This mixture is then added to Mixture 1, andthe resulting mixture is mixed at low speed until it is homogeneous,forming a gel of the invention.

EXAMPLE 2

[0110] A topical cream of the invention is prepared by conventionalpharmaceutical methods. The indicated amounts of the followingingredients are used: Ingredient Amount Purified water 370 grams Whitepetrolatum 250 grams Stearyl alcohol 250 grams Propylene glycol 120grams Sodium lauryl sulfate 10 grams Methylparaben 0.25 gramPropylparaben 0.15 gram Potassium hydroxide 0.01 gram

[0111] The stearyl alcohol and the white petrolatum are melted togetheron a steam bath, and then maintained at a temperature of approximately75° C. The other ingredients are then added, after previously havingbeen dissolved in the purified water and warmed to 75° C., and theresulting mixture is stirred until it congeals into a cream of theinvention.

EXAMPLE 3

[0112] A skin patch of the invention may be prepared by conventionalpharmaceutical methods. A square piece of sterile, finely woven gauzethree centimeters on each side is placed in the center of a square pieceof occlusive surgical adhesive tape five centimeters on each side. Tothe gauze is applied 0.4 mL of the gel of Example 1; the gel is allowedto soak into the gauze. This skin patch of the invention is used withinthree hours of preparation.

EXAMPLE 4

[0113] The gel formulation of Example 1 is provided to patients havingan area of skin hyperpigmentation. The area of skin hyperpigmentation ismeasured and photographed before treatment begins. Each of the patientsis instructed to topically apply the formulation of the invention to thearea of skin hyperpigmentation twice daily for eight weeks. The patientsreturn to the clinic every seven days, when each area of skinhyperpigmentation is again measured and photographed. It is found thatmost of the areas of skin hyperpigmentation are significantly lightenedafter two weeks and that most have regained essentially normal skincolor after eight weeks of treatment, with no scarring or otherundesirable side effects.

EXAMPLE 5

[0114] The skin patches of Example 3 are provided to patients having anarea of skin hyperpigmentation. Each area of skin hyperpigmentation ismeasured and photographed before treatment begins. Each of the patientsis instructed to topically apply a skin patch of the invention over thearea of skin hyperpigmentation, replacing the old patch with a new oneevery 48 hours. The patients return to the clinic every seven days, wheneach area of skin hyperpigmentation is again measured and photographed.It is found that most of the areas of skin hyperpigmentation aresignificantly lightened after two weeks and that most have regainedessentially normal skin color after eight weeks of treatment, with noscarring or other undesirable side effects.

We claim:
 1. A method of lightening the skin of an individual afflictedwith hyperpigmentation, comprising topically applying to an affectedarea of the individual's skin a formulation consisting essentially of apharmacologically active base, at least one pharmaceutically acceptablecarrier, and optionally at least one excipient.
 2. The method of claim1, wherein the hyperpigmentation is selected from the group consistingof keratoses, age spots, idiopathic melasmas, chloasma,hyperpigmentation resulting as a consequence of chemical ingestion orother exposure, hyperpigmentation due to photosensitivity,hyperpigmentation due to genetic makeup, disease-relatedhyperpigmentation, post-lesional scarring, berloque dermatitis, andargyria.
 3. The method of claim 1, wherein the pharmacologically activebase is present in the formulation at a concentration effective toprovide a formulation pH in the range of approximately 7.5 to 13.0. 4.The method of claim 1, wherein the pharmacologically active base ispresent in the formulation at a concentration effective to provide a pHon the skin surface, following topical application of the formulation,in the range of approximately 7.5 to 13.0.
 5. The method of claim 3,wherein the pH is in the range of approximately 8.0 to 11.5.
 6. Themethod of claim 3, wherein the pH is in the range of approximately 8.5to 10.5.
 7. The method of claim 1, wherein the formulation is aqueous.8. The method of claim 7, wherein the aqueous formulation is a cream. 9.The method of claim 7, wherein the aqueous formulation is a gel.
 10. Themethod of claim 7, wherein the aqueous formulation is a lotion.
 11. Themethod of claim 7, wherein the aqueous formulation is a solution. 12.The method of claim 1, wherein the pharmacologically active base is ahydroxide-releasing agent.
 13. The method of claim 12, wherein thepharmacologically active base is selected from the group consisting ofinorganic hydroxides, inorganic oxides, metal salts of weak acids, andmixtures thereof.
 14. The method of claim 13, wherein thepharmacologically active base is an inorganic hydroxide.
 15. The methodof claim 14, wherein the inorganic hydroxide is selected from the groupconsisting of ammonium hydroxide, alkali metal hydroxides, alkalineearth metal hydroxides, and mixtures thereof.
 16. The method of claim15, wherein the inorganic hydroxide is selected from the groupconsisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide,potassium hydroxide, magnesium hydroxide, and mixtures thereof.
 17. Themethod of claim 16, wherein the inorganic hydroxide is sodium hydroxide.18. The method of claim 12, wherein the base is an inorganic oxide. 19.The method of claim 12, wherein the base is a metal salt of a weak acid.20. The method of claim 1, wherein the pharmacologically active base isa nitrogenous base.
 21. The method of claim 1, wherein thepharmacologically active base is an organic base.
 22. The method ofclaim 21, wherein the organic base is selected from primary amines,secondary amines, tertiary amines, amides, oximes, nitrogen-containingheterocycles, and urea.
 23. The method of claim 22, wherein the organicbase is a primary amine, a secondary amine, or a tertiary amine.
 24. Themethod of claim 23, wherein the organic base has the structure NR¹R²R³wherein R¹, R² and R³ are selected from H, alkyl, hydroxyalkyl,alkoxyalkyl, alkenyl, hydroxyalkenyl, alkoxyalkenyl, cycloalkyl,cycloalkyl-substituted alkyl, monocyclic aryl, and monocyclicaryl-substituted alkyl, with the proviso that at least one of R1, R² andR³ is other than H.
 25. The method of claim 23, wherein the organic baseis selected from the group consisting of diethanolamine,triethanolamine, isopropanolamine, triisopropanolamine, dibutanol amine,tributanol amine, N-dodecylethanolamine, N-(2-methoxyethyl)dodecylamine, N-(2,2-dimethoxyethyl)dodecylamine,N-ethyl-N-(dodecyl)ethanolamine, N-ethyl-N-(2-methoxyethyl)dodecylamine,N-ethyl-N-(2,2-dimethoxyethyl) dodecylamine,dimethyldodecylamine-N-oxide, monolauroyl lysine, dipalmitoyl lysine,dodecylamine, stearylamine, phenylethylamine, triethylamine, PEG-2oleamine, PEG-5 oleamine, dodecyl 2-(N,N-dimethylamino)propionate,bis(2-hydroxyethyl)oleylamine, and combinations thereof.
 26. The methodof claim 22, wherein the organic base is an amide.
 27. The method ofclaim 23, wherein the amide has the structure R⁴—(CO)—NR⁵R⁶ where R⁴, R⁵and R⁶ are independently selected from H, alkyl, cycloalkyl,cycloalkyl-substituted alkyl, monocyclic aryl, and monocyclicaryl-substituted alkyl.
 28. The method of claim 27, wherein the amide isselected from the group consisting of hexamethyleneacetamide,hexamethyleneoctamide, hexamethylene lauramide, hexamethylenepalmitamide, N,N-dimethyl formamide, N,N-dimethyl acetamide,N,N-dimethyloctamide, N,N-dimethyldecamide, toluamide,dimethyl-m-toluamide, diethyl-m-toluamide, and combinations thereof. 29.The method of claim 22, wherein the organic base is anitrogen-containing heterocycle.
 30. The method of claim 29, wherein thenitrogen-containing heterocycle is selected from the group consisting of2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone,1-propyl-3-dodecylpyrrolidine, 1-dodecyclazacycloheptan-2-one, ethylenethiourea, hydantoin, oxalylurea, imidazolidilyl urea, N-octadecylmorpholine, dodecylpyridinium, N-dodecylpyrrolidine,N-dodecylpiperidine, N-dodecylhomopiperidine, and combinations thereof.31. The method of claim 1, wherein the formulation is appliedperiodically over an extended time period.
 32. The method of claim 1,wherein the formulation is applied approximately twice weekly.
 33. Themethod of claim 1, wherein the formulation is applied once daily. 34.The method of claim 1, wherein the formulation is applied twice daily.35. The method of claim 1, wherein the formulation is applied on anas-needed basis.
 36. The method of claim 31, wherein said extended timeperiod is at least three months.
 37. The method of claim 36, whereinsaid extended time period is at least four months.
 38. A topicalformulation for lightening the skin of an individual afflicted withhyperpigmentation, consisting essentially of a pharmacologically activebase, at least one pharmaceutically acceptable topical carrier, andoptionally at least one excipient, wherein the active agent is agent ispresent at a concentration sufficient to provide a formulation pH in therange of approximately 7.5 to 13.0.
 39. The formulation of claim 38,wherein the pH is in the range of approximately 8.0 to 11.5.
 40. Theformulation of claim 39, wherein the pH is in the range of approximately8.5 to 10.5.
 41. The formulation of claim 38, wherein the carrier isaqueous.
 42. The formulation of claim 41, selected from the groupconsisting of a cream, a gel, a lotion, and a paste.
 43. The formulationof claim 42, in the form of a cream.
 44. The formulation of claim 42, inthe form of a gel.
 45. The formulation of claim 42, in the form of alotion.
 46. The formulation of claim 42, in the form of a paste.
 47. Theformulation of claim 38, wherein the pharmacologically active base is ahydroxide-releasing agent.
 48. The formulation of claim 47, wherein thepharmacologically active base is selected from the group consisting ofinorganic hydroxides, inorganic oxides, metal salts of weak acids, andmixtures thereof.
 49. The formulation of claim 48, wherein thepharmacologically active base is an inorganic hydroxide.
 50. Theformulation of claim 49, wherein the inorganic hydroxide is selectedfrom the group consisting of ammonium hydroxide, alkali metalhydroxides, alkaline earth metal hydroxides, and mixtures thereof. 51.The formulation of claim 50, wherein the inorganic hydroxide is selectedfrom the group consisting of ammonium hydroxide, sodium hydroxide,calcium hydroxide, potassium hydroxide, magnesium hydroxide, andmixtures thereof.
 52. The formulation of claim 51, wherein the inorganichydroxide is sodium hydroxide.
 53. The formulation of claim 48, whereinthe base is an inorganic oxide.
 54. The formulation of claim 48, whereinthe base is a metal salt of a weak acid.
 55. The formulation of claim38, wherein the pharmacologically active base is a nitrogenous base. 56.The formulation of claim 38, wherein the pharmacologically active baseis an organic base.
 57. The formulation of claim 56, wherein the organicbase is selected from primary amines, secondary amines, tertiary amines,amides, oximes, nitrogen-containing heterocycles, and urea.
 58. Theformulation of claim 57, wherein the organic base is a primary amine, asecondary amine, or a tertiary amine.
 59. The formulation of claim 58,wherein the organic base has the structure NR¹R²R³ wherein R¹, R² and R³are selected from H, alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl,hydroxyalkenyl, alkoxyalkenyl, cycloalkyl, cycloalkyl-substituted alkyl,monocyclic aryl, and monocyclic aryl-substituted alkyl, with the provisothat at least one of R1, R² and R³ is other than H.
 60. The formulationof claim 58, wherein the organic base is selected from the groupconsisting of diethanolamine, triethanolamine, isopropanolamine,triisopropanolamine, dibutanol amine, tributanol amine,N-dodecylethanolamine, N-(2-methoxyethyl) dodecylamine,N-(2,2-dimethoxyethyl)dodecylamine, N-ethyl-N-(dodecyl)ethanolamine,N-ethyl-N-(2-methoxyethyl)dodecylamine, N-ethyl-N-(2,2-dimethoxyethyl)dodecylamine, dimethyldodecylamine-N-oxide, monolauroyl lysine,dipalmitoyl lysine, dodecylamine, stearylamine, phenylethylamine,triethylamine, PEG-2 oleamine, PEG-5 oleamine, dodecyl2-(N,N-dimethylamino)propionate, bis(2-hydroxyethyl)oleylamine, andcombinations thereof.
 61. The formulation of claim 57, wherein theorganic base is an amide.
 62. The formulation of claim 61, wherein theamide has the structure R⁴—(CO)—NR⁵R⁶ where R⁴, R⁵ and R⁶ areindependently selected from H, alkyl, cycloalkyl, cycloalkyl-substitutedalkyl, monocyclic aryl, and monocyclic aryl-substituted alkyl.
 63. Theformulation of claim 62, wherein the amide is selected from the groupconsisting of hexamethyleneacetamide, hexamethyleneoctamide,hexamethylene lauramide, hexamethylene palmitamide, N,N-dimethylformamide, N,N-dimethyl acetamide, N,N-dimethyloctamide,N,N-dimethyldecamide, toluamide, dimethyl-m-toluamide,diethyl-m-toluamide, and combinations thereof.
 64. The formulation ofclaim 57, wherein the organic base is a nitrogen-containing heterocycle.65. The formulation of claim 71, wherein the nitrogen-containingheterocycle is selected from the group consisting of 2-pyrrolidone,1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone,1-propyl-3-dodecylpyrrolidine, 1-dodecyclazacycloheptan-2-one, ethylenethiourea, hydantoin, oxalylurea, imidazolidilyl urea, N-octadecylmorpholine, dodecylpyridinium, N-dodecylpyrrolidine,N-dodecylpiperidine, N-dodecylhomopiperidine, and combinations thereof.66. The formulation of claim 38, further comprising at least oneadditional active agent.